DNA polymerase η contributes to lagging strand synthesis

DNA polymerase eta (pol eta) is best known for its ability to bypass UV-induced thymine-thymine (T-T) dimers and other bulky DNA lesions, but pol eta also has other cellular roles. Here, we present evidence that pol eta competes with DNA polymerases alpha and delta for the synthesis of the lagging strand genome-wide, where it also shows a preference for T-T in the DNA template. Moreover, we found that the C-terminus of pol eta which contains a PCNA-Interacting Protein motif is required for pol eta to function in lagging strand synthesis. Finally, we provide evidence that a pol η dependent signature is also found to be lagging strand specific in patients with skin cancer. Taken together, these findings provide insight into the physiological role of DNA synthesis by pol eta and have implications for our understanding of how our genome is replicated to avoid mutagenesis, genome instability and cancer.DNA聚合酶η（DNA polymerase eta，pol η）最广为人知的功能是能够绕过紫外线诱导的胸腺嘧啶-胸腺嘧啶（T-T）二聚体及其他大体积DNA损伤，但pol η还具备其他细胞生理功能。本研究中，我们提供证据表明，pol η可在全基因组范围内与DNA聚合酶α（DNA polymerase alpha）、DNA聚合酶δ（DNA polymerase delta）竞争参与后随链（lagging strand）的合成，且其在DNA模板（DNA template）中同样偏好识别T-T位点。此外，我们发现，pol η的C端（C-terminus）含有增殖细胞核抗原（PCNA）相互作用蛋白基序（PCNA-Interacting Protein motif），该结构域是pol η参与后随链合成所必需的。最后，我们证实，在皮肤癌患者体内，pol η依赖的特征谱同样呈现后随链特异性。综上，本研究结果为阐明pol η介导的DNA合成的生理功能提供了新的见解，同时也有助于我们理解基因组复制过程中如何规避诱变（mutagenesis）、基因组不稳定（genome instability）及癌症的发生。